The NIMH Collaborative Program on the Psychobiology of Depression (Collaborative Depression Study) is studying the nosology, clinical course and follow-up familial and genetic, and psychosocial factors of affective disorders. The Collaborative Depression Study samples include 955 probands (inpatients and outpatients), 2252 first-degree relatives, 404 matched controls, and 337 spouses of probands. At present, probands are assessed annually and a 6 year re-evaluation of relatives, spouses and controls is nearly completed. This application proposes 1) completion of the 6 year re-evaluation of relatives, spouses and controls; 2) completion of the semi-annual assessment of 250 high-risk relatives; 3) continuation of data analysis of proband and relative data; and 4) continued yearly follow-up of probands. Re-evaluation of relatives, spouses and controls allows prospective assessment of individuals as a function of familial loading, sociodemographic variables and personality. This sample included many individuals with no history of psychiatric disorder prior to the first evaluation. The 6 year re-evaluation permits true prospective assessment of risk for the first onset of affective disorder. For subjects with a history of affective disorder prior to the first evaluation, this sample provides an excellent opportunity to study predictors of future episodes and the clinical course of milder forms. Finally, subjects with alcoholism and anxiety disorders will be used to study predictors of secondary depression. Independent assessments of lifetime psychiatric history at two points in time allow quantification of diagnostic stability. New methods in development will measure sensitivity and specificity of diagnosis, diagnostic validity, familial transmission and secular trends. Two hundred-fifty high-risk subjects are being re-evaluated semi-annually for 3 years; one-quarter are expected to experience depression. A final, blind reassessment of the preceding 3 years will test validity for items assessed in the follow-up of the entire sample of relatives. Furthermore, mild and untreated episodes will be followed identically as the severe episodes in probands permitting more general interpretation of our findings.